Traumatic brain injury (TBI) is a major public health concern, as it is a common result of automobile accidents, falls, and acts of violence. TBI can result in a prolonged loss of cognitive function that may involve several memory, learning, and motor skill deficits. This functional impairment can be attributed to both the initial physical impact and to secondary events that result from the intracranial inflammatory response, including activation of the complement (C) cascade.
Because inflammation is essential for repair and restoration of homeostatic, the challenge is to identify and regulate the components that are neurotoxic. It has been shown that C fragments are present and active within the injured cortex following a lateral fluid percussion (FP) brain injury in the rat. In addition, there is a significant increase in the number of neutrophils within this same region 24 h after trauma (Keeling et al., J. Neuroimmunol., 105:20 (2000)).
C activation results in the formation of several pro-inflammatory mediators and potent leukocyte chemoattractants, including the anaphylatoxins C3a, C4a, and CSa, which propagate the cellular phase of the inflammatory response. Other downstream effector functions of C activation contribute to tissue destruction through formation of the lytic terminal membrane attack complex (MAC), neutrophil chemotaxis, free radical production, cytokine release, and increased vascular permeability (Bellander et al., J. Neurosurg., 85:468 (1996); Frank et al., Immunol. Today, 12:322 (1991); and Kirschfink, Immunopharmacology, 38:51 (1997)).
The vaccinia virus complement control protein (VCP) was the first identified soluble microbial protein with C binding capabilities (Kotwal et al., Science, 250:827 (1990); and Kotwal et al., Nature, 335:176 (1988)). It is related both structurally and functionally to human C regulatory molecules, including soluble C receptor one (sCR1), C4b-binding protein (C4b-BP), Factor H (FH), membrane cofactor protein (MCP), and decay accelerating factor (DAF) (Murthy et al., Cell, 104:301 (2001)). The molecular mimicry of these mammalian proteins that VCP exhibits makes it an important molecule for evasion of host defense against viral infection (Kotwal, J. Leukoc. Biol., 62:415 (1997); and Kotwal, Immunol. Today, 21:242 (2000)).
VCP binds C components C3 and C4, and acts as a cofactor for Factor I cleavage of C3b and C4b, thereby inhibiting downstream activation of both the classical and alternative C pathways (Kotwal et al., Science, 250:827 (1990); and McKenzie et al., J. Infect. Dis., 166:1245 (1992)). It was also recently discovered that VCP can bind to heparin and heparan sulfate proteoglycans (Kotwal et al., Mol. Cell Biochem., 185:39 (1998a); Murthy et al., Cell, 104:301 (2001); Reynolds et al., Advances in Animal Virology, S. Jameel and L. Villarreal (eds), Oxford & IBH Publishing Co., pgs. 343-348 (1999); and Smith et al., J. Virol., 74:5659 (2000)), possibly endowing VCP with an additional anti-inflammatory function, the ability to inhibit cellular migration (Reynolds et al., Advances in Animal Virology, S. Jameel and L. Villarreal (eds), Oxford & IBH Publishing Co., pgs. 343-348 (1999)). It is possible that by binding to heparin and heparin-like molecules on the surface of the endothelial lining of blood vessels, VCP will be able to block the receptors for leukocyte chemotaxis. Therefore, VCP possess two distinct mechanisms of action, one that inhibits the C-mediated effects of inflammation, and one that may more directly inhibit cellular infiltration.
Currently, there is a need for methods for reducing the negative effects of brain trauma.